HIV-1 protease inhibitor (PI) agents have revolutionized HIV care, but have led to marked abnormalities in metabolism. These changes appear to place patients with HIV infection at considerably increased cardiovascular risk. In addition to insulin resistance and hyperlipidemia, endothelial dysfunction occurs and will heighten these risks. Endothelial dysfunction is a critical initial step of atherogenesis that subsequently contributes to the progression and clinical manifestations of atherosclerosis. Preliminary data show that the PI indinavir impairs endothelium-dependent, nitric oxide-mediated, vasodilation in normal subjects. To further define the factors contributing to endothelial dysfunction, identify antiretroviral agents with lesser cardiovascular risk, and identify potential interventions, this project addresses these Specific Aims: (1) Establish the physiologic mediators of endothelial dysfunction caused by indinavir: The hypothesis that insulin resistance mediates endothelial dysfunction due to indinavir will be tested. Normal subjects will receive indinavir for 4 weeks and undergo measurements of endothelium-dependent vasodilatory response both before and during hyperinsulinemia. (2) Compare the effects of PIs with divergent metabolic effects on endothelial function: To test the hypothesis that PIs with lesser tendencies to provoke insulin resistance or dyslipidemia will have lesser effects on endothelial function, normal subjects will be randomized to receive either amprenavir or atazanavir. Similar tests of endothelial function will be performed. (3) Determine if non PI-based combination therapy results in less endothelial dysfunction than a PI-based regimen. The hypothesis that a PI-based antiretroviral combination regimen will induce endothelial dysfunction, but a non-PI-based regimen will not, will be tested. HIV-infected subjects will be randomized to a PI-based regimen that is expected to cause dyslipidemia and insulin resistance, or a non-PI-based regimen that should not. Subjects will cross over to the other therapy after 12 weeks of treatment to establish the reversibility of the endothelial dysfunction. The results of these studies will provide a better understanding of the causes of increased cardiovascular risk among HIV-infected patients, foster the development of antiretroviral drugs that lack adverse effects on cardiovascular risk, and identify potential interventions to test for reduction of risks in HIV-infected patients.